The invention relates to (xe2x88x92)E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine, its salts, and their use as antidiarrhoeal medicaments in man.
The secretory anomalies of the gastro-intestinal tract are responsible, with motor disorders, for the majority of chronic or acute diarrhoeas which, in 1990, were estimated to be the second cause of global mortality, especially in child populations of developing countries.
Chronic diarrhoeas are defined by their generally persistent duration of over two weeks. Their known mechanisms and the diagnostic strategy to be adopted in view of these cases has been documented by M. CERF xe2x80x94Gastroenterol. Clin. Biol, 1992, 16, T 12-T 21. and more recently by M. J. G. FARTHINGxe2x80x94Eur. J. of Gastroenterol. and Hepatol. 1996, 8:157-167. The acute diarrhoeas, a great majority of which are of infectious origin, have likewise been documented by M. CERF and M. HAGIAGE: Diarrhxc3xa9es aiguxc3xas d""origine infectieuse (Acute diarrhoeas of infectious origin),xe2x80x94Editions Techniquesxe2x80x94Encycl. Mxc3xa9d. Chir. (Paris-France), Gastro-entxc3xa9rologie, 9061 A10, 1992, 20pp.; and H. L. DuPONTxe2x80x94Review article: infectious diarrhoeaxe2x80x94Aliment. Pharmacol. Ther. 1994; 8: pp.3-13. Among other causes, the important role of toxinogenesis during bacterial infection is discussed, and, especially, the expression of the pathogenic capacity by the synthesis of thermolabile or thermostable cytotoxins and enterotoxins, which are responsible for secretory diarrhoeas with a hydroelectrolytic component, and whose representative physiopathological model is that of cholera. Other infectious agents are known to cause diarrhoeas of this type, such as Salmonella, Escherichia Coli (E. coli) and Clostridium difficile (C. difficile) strains.
These latter agents, and more particularly C. difficile, are responsible for chronic and abundant secretory diarrhoeas, often of nosocomial origin, in subjects submitted to an intensive antibiotic therapy such as HIV positive patients. In the latter, the particularly incapacitating diarrhoeas are often associated with malabsorption, and contribute to the rapid development of an alarming state of denutrition.
For the treatment of secretory diarrhoeas, rehydration of the patients is recommended and sometimes turns out to be essential. Some compounds have been shown to be active (phenothiazine, chlonidine, bismuth salts) but their sensitive employment because of their secondary effects has led to their generalization being abandoned. The usual symptomatic treatments call for adsorbent compounds (Fuller""s earth), modulators of the intestinal flora and, very widely, compounds called retardants, which are morphinomimetic antidiarrhoeals: loperamide (INN) and diphenoxylate (INN), known inhibitors of the motility of the GI tract: and, in fact, of controversial if not inadvisable utility for certain ailments, among other reasons through the delay which they contribute to the natural evacuation of pathogenic bacteria.
More recently, it has been proposed to treat these diarrhoeas with acetorphan (INN), a synthetic enkephalinase inhibitor dipeptide with antisecretory effect, which maintains the effect of enkephalins, antisecretory endogenous neuropeptides of the intestinal wall, which are normally rapidly hydrolysed in vivo by the enkephalinases which makes their effect fleeting.
As far as the therapy of diarrhoeas of patients infected with HIV is concerned, it is frequently necessary to resort to serious methods, which can only be carried out in an inpatient environment, such as rehydration and renutrition by the enteral or parenteral routes, which are combined with the symptomatic antidiarrhoeal treatment and an antibiotic therapy directed against the possible pathogenic agent. The usual antidiarrhoeal agents only have, most often, a relative and episodic efficacy. Recently, for these ciiarrhoeas and, more generally, cases resistant to conventional therapy, peptides inhibiting motility and gastrointestinal secretion related to somatostatin have been proposed (M. CAMILLERIxe2x80x94Digestion 1996;57 (suppl 1): 90-92 and M. J. G. FARTHINGxe2x80x94Digestion 1996;57 (suppl 1): 107-113). Substitute synthetic compounds for this endogenous mediator are octreotide (INN) and valtreotide (INN), both octapeptides proposed with some success for the treatment of secretory diarrhoeas of AIDS. Although their duration of action is considerably longer than that of somatostatin, these expensive compounds are only active by repeated administration parenterally which leads to prohibitive treatment costs and, because of their mode of administration, makes their use virtually impossible in an outpatient environment. In addition, their lack of specificity, which has been pointed out, can involve secondary effects which dramatically aggravate the state of denutrition of the patients (disorders of the regulation of hydrocarbon metabolism and increase in steatorrhoea).
In addition, certain compounds defined as specific ligands for sigma receptors have shown antisecretory properties suggesting their use in the treatment of diarrhoeas. Thus (+)-N-cyclopropylmethyl-N-methyldiphenyl-1,4-ethyl-1-buten-3-yl-1-amine, or igmesine (INN), and its hydrochloride are disclosed among other compounds in European Patent 0 362 001. The compounds of this patent are defined in vitro as specific ligands for sigma receptors and shown, in vivo, in rats, to be inhibitors of amnesic phenomena caused by scopolamine, and inhibitors of gastroduodenal ulcers caused by the administration of cysteamine, this last activity being connected with their capacity to increase the alkaline duodenal secretion in anaesth,etized animals. In the broad sense, the compounds of this patent are indicated as useful for the treatment of dysfunctions of the gastrointestinal tract such as disorders of peristalsis, of motility, the phenomena of gastro-oesophageal and gastroduodenal reflux as well as for gastric and gastroduodenal ulceration.
Subsequently to these studies, the sigma receptors, whose localization was known in the central nervous system and the immune system, have been demonstrated by F. ROMAN et al. in the gastrointestinal tract of the guinea-pig (Life Sciences 1988, 42, 2217-2222) and then of man (Gastroenterology 1991, 100, A662).
In connection with these localizations, various experiments, among others by J. L. JUNIEN et al. (Neuropharmacology, Volume 30, No. 10, October 1991, pp. 1119-1124) have demonstrated the inhibitory action of igmesine on colonic hypermotility induced by stress via the corticotropin releasing hormone (CRH or CRF) in man. In addition,, P. RIVIERE et al. (Gastroenterol. Clin. Biol. 1991, 15 (2B), A70) show in vitro that igmesine modifies the transmembrane ionic transport through portions of mouse jejunum. This effect, antagonized by haloperidol, involves the participation of sigma receptors. V. J. CARLISI et al. (FASEB J. 1992, 6 (4), A1287) studied the effect of igmesine in vivo in mice, in a model of inflammatory diarrhoea caused by PGE2: at a dose of 30 mg/kg, igmesine, co-administered by the i.p. route with PGE2, delayed by approximately 15 min the appearance of the diarrhoea, an inhibitory effect antagonized by haloperidol, and which, tested for by the oral route, turned out to be zero at a dose of 60 mg/kg. More recently, G. SHI et al. (UEGW 1996xe2x80x94Parisxe2x80x94abstract No. 0786) showed the effect of igmesine at a dose of 200 mg p.o. in man on intestinal hypersecretion induced by PGE2.
On the other hand, the application WO 95/15948 discloses derivatives of 2-arylalkenylazacycloalkanes as ligands for sigma receptors, a process for their preparation and their application in therapeutics. The compounds, their isomers and their addition salts are proposed for the preparation of antipsychotic medicaments and are useful in gastroenterology. The experimental section describes in Example 2E racemic E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine and its hydrochloride and, in addition, mentions without specific experimental results that the compounds of the application are active on secretory diarrhoeas induced in mice by Salmonella lipopolysaccharicle (LPS), which suggests their use in the treatment of secretory diarrhoeas of varying aetiologies.
Overcoming the difficulties and uncertainties of the prior art; as set out, the present invention proposes for the purposes of symptomatologic treatment of secretory diarrhoeas the use, in appropriate medicamentous forms, of a novel optically active compound, which is a ligand for sigma receptors, and whose spectrum of antidiarrhoeal properties is particularly remarkable and distinguishes it formally from the prior art.
The subject of the invention by way of novel compound is optically pure (xe2x88x92)E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine (I) of formula 
its addition salts with pharmaceutically acceptable acids and a process for their preparation.
It likewise relates, by way of medicaments, to (xe2x88x92)E2-(3,4-dichlorocinnamyl)-l-cyclopropylmethyl-piperidine (I) and its, addition salts as well as their use in the preparation of pharmaceutical compositions intended for the treatment of diarrhoeas. It also comprises the medicamentous compositions comprising by way of active principle (xe2x88x92)E-2(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine (I) or its addition salts in therapeutically efficacious quantity.
In first place, the invention is directed at optically pure (xe2x88x92)E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine (I) and its addition salts with pharmaceutically acceptable acids.
Optically pure is understood as meaning that the product is practically free of its optical antipode and is at least of an optical purity of 95% and, preferably, equal to or greater than 98% in levorotatory eutomer, this being determined by appropriate analytical means.
Pharmaceutically acceptable addition salts are understood as meaning those inorganic or organic salts, and their possible isomers, shown to be non-toxic in the therapeutically customary doses of which, for example, a list is presented in J. Pharm. Sci., 1977, Volume 66, pp. 119. Non-limiting examples are acetic, benzenesulphonic, camphorsulphonic, citric, ethanesulphonic, hydrdbromic, lactic, maleic, malic, methanesulphonic, mucic, nitric, pamoic, phosphoric, salicylic, stearic, succinic, sulphuric or tartaric acid and hydrochloric acid, which is preferred. In another aspect, the invention relates to a process for the preparation of optically pure (xe2x88x92)E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine (I) which consists either in resolving the corresponding racemic compound described in Example 2E of the application WO 95/15948, or in carrying out the chemical synthesis starting from (+) E-2-(3,4-dichlorocinnamyl)piperidine (III), itself obtained, according to the application WO 95/15948, by resolution of the corresponding racemic compound described in preparation 2E of the same patent application.
Resolution of the racemic compound corresponding to the product of the invention consists in using an optically active acid to obtain, with the racemate, diastereoisomeric addition salts which are separated by crystallization, and from which the two resolved enantiomers are generated by appropriate treatment. Acids currently used for the preparation of such salts are, as non-limiting examples, the enanticimers of xcex1-phenylglycine, xcex1-phenylalanine, malic, mandelic and tartaric acids, of camphanic acid or alternatively of xcex1-methoxy-xcex1-trifluoromethylacetic acid. An alternative method of resolution is the direct resolution of the racemic compound by high-performance liquid chromatography on a column containing, for example, as stationary phase a cellulose polymer grafted with carbamate groups such as the phase CHIRACEL OD (Daicel) and carrying out an elution with hexane containing a small quantity of triethylamine.
However, the preferred process is an adaptation of the methodology described in the application WO 95/15948 and consists in carrying out the resolution of (+/xe2x88x92) E-2-(3,4-dichlorocinnamyl)piperidine via the eutomeric diastereoisomeric salt with N-acetyl-L-phenylalanine, which, purified and treated, leads to (+) E-2-(3,4-dichlorocinnamyl) piperidine (III), and then in acylating (III) with cyclopropanecarboxylic acid to obtain (+) E-2-(3,4-dichlorocinnamyl)-1-cyclopropanecarbonylpiperidine (II), and then, in reducing (II) with a metallic or organometallic hydride to obtain (xe2x88x92)E-2-(3,4-dichlorocinnamyl)-1-cyclo-propylmethylpiperidine (I) of suitable optical purity and, optionally, in making a pharmaceutically acceptable salt: 
At the resolution stage, the recovery and the purification of the (xe2x88x92) antipode of the intermediate compound (III) allows, according to the same process, the distomer of the compound of the invention to be prepared, namely (+)E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine synthesized as comparison product.
The compound which is the subject of the invention and its salts have remarkable pharmacological properties, indicative of their usefulness in the form of medicaments for the treatment of secretory diarrhoeas in man. Although in vitro its affinity for sigma receptors is not stereospecific but of comparable intensity to that of its antipode, totally unexpectedly, the (xe2x88x92)E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine eutomer (I) shows in vivo, in various representative models of toxigenic secretory diarrhoea, a very strong and stereoselective antidiarrhoeal activity.
Thus, the levorotatory eutomer appears from 4 to more than 50 times more active, by the oral route in mice, than its parent racemate in the models of secretory diarrhoea caused by Salmonella lipopolysaccharide (LPS), the thermostable toxin of E. coli and the A and B toxins of C. difficile, without acting on the transit. Likewise, the eutomer turns out to be close to 50 times more active than the racemate by the oral route, in rats, on the inhibition of the intestinal secretion caused by cholera toxin.
In mice, by the oral route in the models of toxigenic secretory diarrhoeas which have just been presented, when it is compared to published compounds or those potentially capable of treating secretory diarrhoeas, the eutomer which is the subject of the invention turns out to be:
from 66 to more than 4000 times more active than loperamide,
from 75 to more than 1400 times more active than igmesine,
and, on diarrhoea caused by LPS, more than 6000 times more active than acetorphan.
Finally, compared to the enantiomers described in the application WO 95/15948 and which turn out to be equally active in vivo in diarrhoea caused by LPS, the study as a function of the dose shows, for the comparison products (xe2x88x92) E-2-cinnamyl-1-cyclopropylmethylpyrrolidine (Example 1.3 of WO 95/15948) and (xe2x88x92) E-2-cinnamyl-l-cyclopropylmethyl-piperidine (Example 2A.3), a progressive effect which, after a maximum, decreases significantly, whereas, differently, the eutomer shows a progressive effect followed by a stage in which this activity is maintained, which is demonstrative of a safety of medical use and of a therapeutic aid, contrary to the comparison products for which the zone of active concentrations, or therapeutic window, is narrow and leads to a dosage which is difficult to handle and thus to a risk of inefficacy.
These studies, expanded on in the experimental section, demonstrate the particularly interesting antidiarrhoeal activity of (xe2x88x92)E-2-(3,4-dichlorocinnamyl)-1-cyclopropyl-methylpiperidine (I) and of its salts and their utility in the preparation of pharmaceutical forms which can be administered to mammals including humans by routes appropriate to the pathology and condition of the subject. Thus, the medicaments can be administered by the parenteral, transdermal or transmucosal route in conventionally known forms. However, the pharmaceutical forms adapted to outpatient treatments are preferred and especially those intended for administration by the oral route.
The pharmaceutical compositions according to the invention which contain a therapeutically efficacious quantity of compound (I) or of one of its salts, are appropriate for the treatment of diarrhoeas which may be commonplace, such as those of infants or of travellers, and which may be acute and/or persistent and of varying aetiology in which the secretory component can just as well result from a decrease in absorption as from intestinal hypersecret ion.
Thus, the compositions of the compound (I) are indicated for the treatment of diarrhoeas of inflammatory origin (Crohn""s disease, post-radiotherapy enterites), of obstructions by lymphoid hyperplasia or alternatively of anti-cancer chemotherapy.
Likewise, these compositions are appropriate for the symptomatic treatment of hypersecretory diarrhoeas such as those following neuroendocrine tumour conditions (Zollinger-Ellison syndrome, VIPoma, somatostatinoma, carcinoid syndrome), of viral, including HIV, or bacterial infections, or even of congenital dysfunctions or those caused by cathartic drugs, and during hypersecretions of intestinal inflammatory syndromes.
The good tolerance to the product shown in the preliminary tests justifies, for treatments of two to three weeks, a daily dosage of 5 to 50 mg and, in exceptional cases, for aggressive treatments of short duration up to 100 mg. However, the majority of diarrhoeal conditions treated are improved by daily dosages of 10 to 30 mg, the product being administered by the oral route, divided into two to four administrations per 24 hours.
The product is administered in various pharmaceutical forms, containing per unit from 1.25 to 25 mg of the compound (I) or of one of its salts, especially of its hydrochloride; these forms can be, as non-limiting examples, tablets, coated tablets, capsules, gelules, powders, solutions, suspensions or gels.
For the so-called solid forms, the compound (I) or its salt may represent from 1 to 90% by weight of the finished form, the pharmaceutically acceptable excipients representing from 99 to 10%. For liquid forms or those considered as such, the active principle can represent from 0.1 to 10% by weight of the finished form, the liquid phase representing from 99.9 to 90% by weight.